Cancer is among the leading causes of morbidity and mortality worldwide, with approximately 14 million new cases and 8.2 million cancer related deaths in 2012 (World Cancer Report 2014 and de Martel C, et al. (2012) Lancet Oncol 13(6):607-615) and the number of new cases is expected to rise by about 70% over the next 2 decades. Advances in the management of cancers have improved the overall outlook of patients with metastatic malignancies but chemotherapy remains a mainstay of treatment for most common cancers. Virtually all patients develop resistance to chemotherapy after prolonged exposure given the first order kinetics of cytotoxics that generally cannot eradicate cancer. Understanding the mechanisms of this resistance presents new opportunities to improve the therapeutic index of cytotoxic agents and to identify novel drug targets.
Many chemotherapeutic agents function through damaging DNA in tumor cells and therefore the natural DNA repair functions in these cells act against the effect of the chemotherapy. This problem has led to introduction of combination therapies, in which the administration of a chemotherapeutic agent is accompanied by the administration of inhibitor(s) of key molecular components of the DNA repair pathways (Dawar et al., Curr Med Chem. 2012; 19(23):3907-21; ASCO Clin Oncol 27:18s, 2009 (suppl. abstr. 3)). A large proportion of cytotoxic agents exert their effect through DNA damage. Thus, DNA repair pathways represent their most likely mechanisms of resistance and potential drug targets. Base excision repair is the predominant pathway for single strand break (SSB) damage repair utilizing a family of related enzymes termed poly-(ADP-ribose) polymerases (PARP), which are activated by DNA damage (Luo and Kraus W L (2012) Genes Dev 26(5):417-432).
Because of its key role in DNA base excision repair, PARP1 is an important target for such inhibitors. PARP inhibitors that are now under investigation in clinical trials include olaparib, niraparib, and BMN 673, all to be tested in upcoming Phase III trials; veliparib (ABT-888) in Phase II trials; rucaparib in Phase I/II development; and CEP-9722 and E7016 in Phase I trials (Fuerst, M. “More Than a Handful of PARP Inhibitors in Development to Treat Hereditary Breast Cancer,” Oncology Times 2014, Volume 36(2): 50-51). Olaparib received FDA approval for use in the treatment of platinum-resistant ovarian cancer in 2015. There is evidence (Matthew et al., Mol Cancer Res; 12(8): 1069-1080, 2014: Horton et al., Mol. Cancer Res. 12: 1128-1139, 2014) that because of the multi-factorial nature of the base excision repair process, where PARP1 is a key element, the therapeutic effects and outcomes are sensitive to all changes, modifying the optimal balance in the therapy-carrying pathways and processes. A need remains for methods that identify those subjects with cancer that can be treated with PARP1 inhibitors.